Fenebrutinib Shows 12% Reduction in Disability Progression vs Ocrelizumab in PPMS Trial

Genentech announced new late-breaking data from the Phase III FENtrepid study showing the investigational Bruton's tyrosine kinase (BTK) inhibitor fenebrutinib met its primary endpoint of non-inferiority compared to ocrelizumab in reducing disability progression in patients with primary progressive multiple sclerosis (PPMS). Fenebrutinib showed a 12% reduction in the risk of disability progression compared to ocrelizumab, the only approved medicine for PPMS, as measured by the time to onset of 12-week composite confirmed disability progression (cCDP12) (hazard ratio 0.88; 95% confidence interval: 0.75, 1.03) with curves separating as early as 24 weeks.

The 12-week composite confirmed disability progression measure (cCDP12) incorporates three measures of disability: total functional disability measured by the Expanded Disability Status Scale (EDSS), walking speed measured by the timed 25-foot walk (T25FW), and upper limb function measured by the nine-hole peg test (9HPT). Any increase in disability is retested 12 weeks later to confirm. A consistent treatment effect on cCDP12 was observed across patient subgroups and for the entire treatment duration, which lasted at least 120 weeks and up to 240 weeks for some participants.

The strongest treatment effect was observed on the risk of worsening on the 9HPT by 26% (HR 0.74; 95% CI: 0.56, 0.98) compared to ocrelizumab. Additionally, a post-hoc analysis showed that fenebrutinib was superior to ocrelizumab on a composite endpoint including two of the three components of cCDP12 (EDSS and 9HPT), with a 22% reduction in risk (HR 0.78; 95% CI: 0.64, 0.95).

Fenebrutinib is an experimental oral drug in a class of medications known as Bruton's tyrosine kinase (BTK) inhibitors. BTK is an enzyme that is important for many immune B cells as well as immune cells in the brain and spinal cord, known as microglia. This means that BTK inhibitors can target the immune cells that are thought to be involved in disease progression inside and outside the brain. Fenebrutinib binds to BTK reversibly, unlike other BTK inhibitors tested in MS such as evobrutinib and tolebrutinib, which bind to BTK in a permanent way.

In general, the safety profile of fenebrutinib was similar to that of ocrelizumab. Adverse events commonly (≥10%) observed in the fenebrutinib group were comparable to ocrelizumab: infections (67.0% vs 70.9%), nausea (12.0% vs 7.1%) and hemorrhage (10.2% vs 8.1%). Transient and reversible liver enzyme elevations were observed more often in the fenebrutinib group (13.3% vs 2.9%), and all cases resolved after study drug discontinuation. No Hy's law cases (an indicator for potential severe liver injury) were observed.

Serious adverse events were reported in 19.1% of patients receiving fenebrutinib (vs 18.9% on ocrelizumab) and led to 4.3% withdrawing from treatment (vs 3.0% on ocrelizumab). In the FENtrepid study there were 1.4% fatal cases in the fenebrutinib arm vs 0.2% in the ocrelizumab arm, all of which were assessed as unrelated to the study treatment by the investigators and no pattern was observed in timing or cause. Epidemiological studies have shown that fatality rates are higher in people living with MS compared to the general population.

Results were shared as a late-breaking oral presentation at the Americas Committee for Treatment and Research in Multiple Sclerosis (ACTRIMS) Forum 2026 in San Diego, California on February 7. These data follow Genentech's announcement in November 2025 that the FENtrepid study and the first of two Phase III relapsing multiple sclerosis (RMS) studies (FENhance 2) met their primary endpoints. Regulatory submission for fenebrutinib in both PPMS and RMS is planned following the Phase III FENhance 1 readout, expected mid first half of 2026. These results will form part of submissions to regulators, to potentially provide a new oral treatment option for people with primary progressive MS.